Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
<h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23209787/?tool=EBI |
| _version_ | 1818574602051256320 |
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| author | Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius |
| author_facet | Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius |
| author_sort | Christian Gytz Ammitzbøll |
| collection | DOAJ |
| description | <h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement system through the lectin pathway. The lectin pathway is multifaceted with activities spanning from complement activation to coagulation, autoimmunity, ischemia-reperfusion injury and embryogenesis. Our aim was to explore associations between SNPs in FCN1, encoding M-ficolin and corresponding protein concentrations, and the impact of non-synonymous SNPs on protein function.<h4>Principal findings</h4>We genotyped 26 polymorphisms in the FCN1 gene and found 8 of these to be associated with M-ficolin levels in a cohort of 346 blood donors. Four of those polymorphisms were located in the promoter region and exon 1 and were in high linkage disequilibrium (r(2)≥0.91). The most significant of those were the AA genotype of -144C>A (rs10117466), which was associated with an increase in M-ficolin concentration of 26% compared to the CC genotype. We created recombinant proteins corresponding to the five non-synonymous mutations encountered and found that the Ser268Pro (rs150625869) mutation lead to loss of M-ficolin production. This was backed up by clinical observations, indicating that an individual homozygote of Ser268Pro would be completely M-ficolin deficient. Furthermore, the Ala218Thr (rs148649884) and Asn289Ser (rs138055828) were both associated with low M-ficolin levels, and the mutations crippled the ligand-binding capability of the recombinant M-ficolin, as indicated by the low binding to Group B Streptococcus.<h4>Significance</h4>Overall, our study interlinks the genotype and phenotype relationship concerning polymorphisms in FCN1 and corresponding concentrations and biological functions of M-ficolin. The elucidations of these associations provide information for future genetic studies in the lectin pathway and complement system. |
| first_indexed | 2024-12-15T00:28:44Z |
| format | Article |
| id | doaj.art-8f3eb45e57f44e1dae7f89c142531344 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-15T00:28:44Z |
| publishDate | 2012-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-8f3eb45e57f44e1dae7f89c1425313442022-12-21T22:42:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e5058510.1371/journal.pone.0050585Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.Christian Gytz AmmitzbøllTroels Rønn KjærRudi SteffensenKristian Stengaard-PedersenHans Jørgen NielsenSteffen ThielMartin BøgstedJens Christian Jensenius<h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement system through the lectin pathway. The lectin pathway is multifaceted with activities spanning from complement activation to coagulation, autoimmunity, ischemia-reperfusion injury and embryogenesis. Our aim was to explore associations between SNPs in FCN1, encoding M-ficolin and corresponding protein concentrations, and the impact of non-synonymous SNPs on protein function.<h4>Principal findings</h4>We genotyped 26 polymorphisms in the FCN1 gene and found 8 of these to be associated with M-ficolin levels in a cohort of 346 blood donors. Four of those polymorphisms were located in the promoter region and exon 1 and were in high linkage disequilibrium (r(2)≥0.91). The most significant of those were the AA genotype of -144C>A (rs10117466), which was associated with an increase in M-ficolin concentration of 26% compared to the CC genotype. We created recombinant proteins corresponding to the five non-synonymous mutations encountered and found that the Ser268Pro (rs150625869) mutation lead to loss of M-ficolin production. This was backed up by clinical observations, indicating that an individual homozygote of Ser268Pro would be completely M-ficolin deficient. Furthermore, the Ala218Thr (rs148649884) and Asn289Ser (rs138055828) were both associated with low M-ficolin levels, and the mutations crippled the ligand-binding capability of the recombinant M-ficolin, as indicated by the low binding to Group B Streptococcus.<h4>Significance</h4>Overall, our study interlinks the genotype and phenotype relationship concerning polymorphisms in FCN1 and corresponding concentrations and biological functions of M-ficolin. The elucidations of these associations provide information for future genetic studies in the lectin pathway and complement system.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23209787/?tool=EBI |
| spellingShingle | Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. PLoS ONE |
| title | Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. |
| title_full | Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. |
| title_fullStr | Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. |
| title_full_unstemmed | Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. |
| title_short | Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin. |
| title_sort | non synonymous polymorphisms in the fcn1 gene determine ligand binding ability and serum levels of m ficolin |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23209787/?tool=EBI |
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